The present invention relates to compounds which bind to the xcex12-adrenoceptor. More particularly, the present invention relates to certain imidazoethyl thiophenes/thiazoles or benzothiophenes and analogues which are xcex12-adrenoceptor modulators.
xcex12-adrenoceptor modulators are useful to treat a variety of conditions, including, hypertension, glaucoma, sexual dysfunction, depression, attention deficit hyperactivity disorder, the need for anesthesia, cardiac arrythmia and the need for analgesia. Particularly, xcex12-adrenoceptor agonists are well known analgesics. xcex12-adrenoceptor antagonists have potential as antidepressants in their own right or as adjunct therapies to traditional inhibitors of monoamine reuptake.
Clonidine is a centrally acting xcex12-adrenoceptor agonist with wide clinical utility as an antihypertensive agent. Clonidine is believed to act by inhibiting the release of norepinephrine from sympathetic nerve terminals via a negative feedback mechanism involving xcex12-adrenoceptors located on the presynaptic nerve terminal. This action is believed to occur in both the central (CNS) and peripheral (PNS) nervous systems. More recently, the role of xcex12-adrenoceptor agonists as analgesic agents in humans and antinociceptive agents in animals has been demonstrated. Clonidine and other xcex12-adrenoceptor agonists have been shown to produce analgesia through a non-opiate mechanism and, thus, without opiate liability. However, other behavioral and physiological effects were also produced, including sedation and cardiovascular effects. 
Medetomidine, detomidine, and dexmedetomidine are xcex12-adrenoceptor agonists. Dexmedetomidine is used clinically in veterinary medicine as a sedatives/hypnotic for pre-anaesthesia. These compounds are hypotensive in animals and in humans, but the magnitude of this cardiovascular effect is relatively insignificant. 
U.S. Pat. No. 3,574,844, Gardocki et al., teach 4-[4 (or 5)-imidazolylmethyl]-oxazoles as effective analgesics. The disclosed compounds are of the general formula: 
Compounds of this type are insufficiently active and suffer from unwanted side effects.
U.S. Pat. No. 4,913,207, Nagel et al., teach arylthiazolylimidazoles as effective analgesics. The disclosed compounds are of the general formula: 
Compounds of this type are insufficiently active and suffer from unwanted side effects.
WO92/14453, Campbell et al., teach 4-[(aryl or heteroaryl)methyl]-imidazoles as effective analgesics. The disclosed compounds are of the general formula: 
The disclosed compounds are insufficiently active and suffer from unwanted side effects.
Kokai No. 1-242571, Kihara et al., disclose a method to produce imidazole derivatives for use, among other uses, as antihypertensive agents. 
A single mixture of compounds meeting the above formula was reportedly produced by the inventive method. This was a mixture of 4-(2-thienyl)-methylimidazole and 4-(3-thienyl)-methylimidazole represented by the following formula: 
The disclosed compounds are insufficiently active and suffer from unwanted side effects.
U.S. Pat No. 5,621,113 and U.S. Pat No. 5,750,720, Boyd and Rasmussen disclose substituted 2 and 3-thienyl methylimidazoles as effective analgesic agents. 
Many potent and selective xcex12 antagonists, such as idazoxan, have been synthesized and evaluated in limited clinical trials as antidepressants. (J. Med. Chem. 1995, 38 (23), 4615.). Mirtazapine is a closely related analog of the established antidepressant mianserin. This compound has been shown to be an antagonist at xcex12 receptors snd exhibits antidepressant activity in vivo. (Exp. Opin. Invest. Drugs 1995, 4 (10), 945.). An agent with the dual profile of a 5 HT reuptake inhibitor and an a2 antagonist might serve to enhance synaptic concentrations of 5-HT relative to that achievable through 5-HT uptake inhibition alone and in turn produce a more effective antidepressant response. A novel series of compounds with such a profile was found to possess putative antidepressant effects in vivo (J. Med. Chem. 1997, 40 (7), 1049; Bioorg. Med. Chem Lett. 1995, 5, 2287.; Drug. Dev. Res. 1995, 35, 237.; Drug. Dev. Res. 1995, 35, 246.)
Briefly, there is provided by the present invention compounds which are xcex12-adrenoceptor modulators of the formula: 
where
Z is CH or N; and
X is independently selected from the group consisting of hydrogen, C1-4alkyl, bromine, chlorine, iodide, trifluoromethyl, C1-4alkoxy and nitro.
The compounds of the present invention are prepared by the methods shown in Scheme 1. Scheme 1 is drawn to depict only thiophene, but the thiophene of this scheme could in each instance be replaced with the equivalent benzothiophene to produce the benzothiophene end product. In Scheme 1, an appropriately substituted thiophene aldehyde A1 is reduced with an appropriate reducing agent such as NaBH4 in a solvent such as methanol to give the thiophene alcohol A2. This thiophene alcohol A2 is converted to the thiophene bromide A3 by reaction with CBr4 /PPh3. This bromomethyl thiophene A3 is then reacted with PPh3 in a solvent such as THF to yield the thiophene phosphonium salt A4. This phosphonium salt undergoes Wittig reaction with N1-trityl-imidazole-4-carboxaldehyde in the presence of an appropriate base such as sodium methoxide in methanol or lithium hexamethyldisilazide in THF. The resultant mixture of cis and trans isomers A5 are deprotected under acidic conditions such as with acidic methanol or trifluoroacetic acid in dichloromethane. The desired product is then obtained by catalytic reduction to yield the appropriately substituted imidazoethyl thiophenes A6. 
Alternatively, the phosphonium salt of the thiophene A4 can be obtained by direct reaction of the appropriately substituted hydroxymethylthiophene A2 with triphenylphosphine hydrobromide in trichloromethane as illustrated in Scheme 2. 
The thiazoles can be made according to the procedure of Scheme 1 from an equivalent thiazole phosphonium salt A4 to an equivalent imidazoethylthiazole A6. To obtain the equivalent thiazole phosphonium salt A4 the procedure disclosed by Williams and Brooks Tetrahedron Letters 1996, 983 should be employed. In the case where R is hydrogen, C1-4alkyl, C1-4alkoxy and trifluoromethyl, the appropriately substituted thiophene alkenyl imidazole A5 may be produced and the substituent in question will stably endure the reactions of Scheme 1 or Scheme 2 to arrive at target products A6. In the case where R is chlorine, bromine and nitro, the saturated product A6 may be obtained from the unsaturated intermediate A5 by alternate reduction conditions such as borane/methylsulfide or triethylsilane/trifluoroacetic acid.
The compounds of the present invention may be used to treat a medical condition as named herein, such as, mild to moderate pain in warm-blooded animals, such as, humans by administration of an effective dose. The dosage range would be from about 10 to 3000 mg, in particular about 25 to 1000 mg or about 100 to 500 mg, of active ingredient 1 to 4 times per day for an average (70 kg) human although it is apparent that activity of individual compounds of the invention will vary as will the pain being treated. In regard to the use of these xcex12-adrenoceptor modulators to treat hypertension, glaucoma, sexual dysfunction, depression, attention deficit hyperactivity disorder, the need for anesthesia and cardiac arrythmia, a therapeutically effective dose can be determined by persons skilled in the art by use of established animal models. Pharmaceutical compositions of the invention comprise the formula (I) compounds as defined above, particularly in admixture with a pharmaceutically-acceptable carrier.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the invention or salt thereof as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
The pharmaceutically acceptable salts referred to above generally take a form in which the imidazolyl ring is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, famaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic or saccharic.
The activity of compounds of the invention as xcex12 modulators may be demonstrated by the in vivo and in vitro assays as described below:
Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) are sacrificed by cervical dislocation and their brains removed and placed immediately in ice cold HEPES buffered sucrose. The cortex is dissected out and homogenized in 20 volumes of HEPES sucrose in a Teflon(trademark)-glass homogenizer. The homogenate is centrifuged at 1000 g for 10 min, and the resulting supernatant centrifuged at 42,000 g for 10 min. The resulting pellet is resuspended in 30 volumes of 3 mM potassium phosphate buffer, pH 7.5, preincubated at 25 xc2x0 C. for 30 min and recentrifuged. The resulting pellet is resuspended as described above and used for the receptor binding assay. Incubation is performed in test tubes containing phosphate buffer, 2.5 mM MgCl2, aliquots of the synaptic membrane fraction, the ligand 3H-para-aminoclonidine and test drug at 25xc2x0 C. for 20 min. The incubation is terminated by filtration of the tube contents through glass fiber filter sheets. Following washing of the sheets with 10 mM HEPES buffer, the adhering radioactivity is quantified by liquid scintillation spectrometry.
Binding of the test drug to the receptor is determined by comparing the amount of radiolabeled ligand bound in control tubes without drug to the amount of radiolabeled ligand bound in the presence of the drug. Dose-response data are analyzed with LIGAND, a nonlinear curve fitting program designed specifically for the analysis of ligand binding data. This assay is described by Simmons, R. M. A., and Jones, D. J., Binding of [3H-]prazosin and [3H-]p-aminoclonidine to (xcex1-Adrenoceptors in Rat Spinal Cord, Brain Research 445:338-349, 1988.
Mouse Acetylcholine Bromide-Induced Abdominal Constriction Assay (MAIT)
The mouse acetylcholine bromide-induced abdominal constriction assay, as described by Collier et al. in Brit. J. Pharmacol. Chem. Ther., 32: 295-310, 1968, with minor modifications was used to assess analgesic potency of the compounds herein. The test drugs or appropriate vehicle were administered orally (p.o.) and 30 minutes later the animal received an intraperitoneal (i.p.) injection of 5.5 mg/kg acetylcholine bromide (Matheson, Coleman and Bell, East Rutherford, N.J.). The mice were then placed in groups of three into glass bell jars and observed for a ten minute observation period for the occurrence of an abdominal constriction response (defined as a wave of constriction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs). The percent inhibition of this response to a nociceptive stimulus (equated to % analgesia) was calculated as follows: The % Inhibition of response, i.e., % analgesia is equal to the difference between the number of control animals responding and the number of drug-treated animals responding times 100 divided by the number of control animals responding.
At least 15 animals were used for control and in each of the drug treated groups. At least three doses were used to determine each dose response curve and ED50 (that dose which would produce 50% analgesia). The ED50 values and their 95% fiducial limits were determined by a computer assisted probit analysis.
Tables 1-3 list compounds made in the examples below with certain biological and physical data.
The following Examples illustrate the invention: